Aromatic esters of amino alcohols and process of manufacture



Patented Nov. 29, 1932 UNITED STATES. PATENT OFFICE CHARLES MANNICH, OF IBERLIN-STEGLITZ, GERMANY I AROMATIC ES'IEBS OF AMING ALGOHOLS AND PROCESS OF MANUFACTURE No Drawing. Application filed October 3, 1930, Serial No. 488,289, and in Germany November 1, 1929.

It has been found that the aromatic esters of amino alcohols of the formula R I R CHr-N a omon (B being hydrogen or alkyl) possess particularly good properties as products for local anaesthesia. The alcohol bases used as starting material are derived from aldehyde bases by reduction for instance with sodium amalgain in slightly acetic acid solution, the said aldehyde bases bein obtained by condensation of aldehydes of the general formula with formaldehyde and primary or secondary aliphatic amines. By allowing aromatic acids or derivatives, preferably acid chlorides, to act upon the alcohol bases the esters are obtained easily and with a good yield, said esters forming well crystallized hydrochlorides which are stable also in hot water.

E mample 1 5.5 parts of 3-dimethylamino-2-dimethylpropane-l-ol (boiling point 166168 C. at T 7 60 mm.) are dissolved in 6 parts of chloroform and, while cooling, a solution of 6 parts of benzoylchloride in a. little chloroform is added. The reaction product is then heated for an hour to C. and precipitated with 40 rfl er, :The precipitated hydrochloride is re- 3-dlmethylaminoz-dlinebenzoylchloride thyl-propsne-l ol 3-dimethylamino-2-dimethyl-1-benzoylhydroxypropane hydrochloride -HCI , 1 Example 2 5.5 parts of 3-dimethylamino-2-dimethylpropane-l-ol are dissolved in 6parts ofchloroform and a solution of 12 parts of p-nitrobenzoylchloride is added. After having heated for an hour to 40 C. the chloroform. is'removed in vacuo and the residue is stirred with ether until the salt becomes crystalline. It is recrystallized from alcohol and melts at 180 C. 1 part of the product thus purified is dissolved in 20 parts of water, 0.3 part of a 1% solution of palladium chloride is added 70 and the product is shaken with hydrogen under pressure of 2 atmospheres. When about 220 com. of hydrogen have been taken up, the product is filtered and from the warm solution the base is precipitated with a solution 75 of sodium hydroxide. It crystallizes from petrol-ether, its melting point being 7 9-80 C. The crystalline hydrochloride with the melting point of 93 C. is obtained therefrom in the usual manner with alcoholic hydrochloric acid and ether. The reactions are illustrated as follows:

S-dIethyIamino-Z-dirnethyl- 3-dimethylamino-2-dimethyl-l-pnltrobenzoylhydroxypropane hydrochloride I CH:

I CHr-N l O\ OH; -H (EH-2H: O

orno-o NH;

3dimethylamlno-2-dimethyI-1-p-aminobenzoylhydroxypropane hydrochloride Example 3 4 parts of 3-diethylamino-2-dimethyl-propane-l-ol (boiling point 90-91 G. at 12 mm.) are diluted with 5 parts of chloroform and while cooling 6 parts of benzoylchloride are added. The reaction product is left standingfor a few hours and then precipitated with ether. The precipitated hydrochloride of 3- diethylamino-Q-dimethyl 1 -benzoylhydroxypropane is recrystallized from absolute alcohol with an addition of ether and melts at 131132 C. The reaction is illustrated as follows OH: OH

benzoylchlorlde propane-L01 CHz-N CIHI CH: CHaO-C 3-diethylamino- 2-dimethyI-l-benzoylhydroxypropane hydrochloride Ewample If a solution of 5.5 parts of pnitrobenzoylchloride in chloroform is added to-parts of 3-diethylamino-2-dimethyl-propane-1-ol, the

hydrochloride of 3-diethylamino-2-dimethyl- 1-p-nitrobenzoylhydroxypropane is formed while heating. The reaction product is left standing for a few hours, the compound is precipitated with ether and recrystallized from isopropyl alcohol (melting point 160 (1). 1 part of this product is dissolved in 15 parts of water and after the addition of 0.3 part of a 1% solution of palladium chloride and 0.1 part of animal charcoal hydrated under pressure of 2 atmospheres. When thetaking up of hydrogen is terminated, the product is filtered and the solution evaporated in vacuo. The residue is recrystallized from isopropyl alcohol. The 3- diethylamino-2-dimethyl-lpaminobenzoylhydroxypropane hydrochloride melts at 195 196 C. The reactions are illustrated as follows:

. 01H: on, om-N 0 H1 4 OH:- OH

I nitrobenzoylchloride 3-diethylam1no-2-diemethy1- i propane-J-ol CHz-N CHr-O-C O- 3-diethylamino-2-dimethyl-l-p-nitrobenzoylhydroxypropane hydrochloride CHN CsHs

CH1- 0- C 0 on! N01 3-dieth lamiuo-Z-dimethyl-l-pnitro nzoylhydroxypropane hydrochloride 0H, CHa-N C CzHs 3-diethylamino-2-dimethy1-1-p-aminobenzolyhydroxypropane hydrochloride Ewample 5 To a solution of 4 parts of 3-dimethylamino-2-isopropyl-propane-1-ol in 5 parts of chloroform is added slowly while cooling a solution of 5 parts of p-nitrobenzoylchloride in as little chloroform as possible. Within the course of a few hours the hydrochloride of 3-dimethylamino-2-isopropyl-1-p-nitrobenzoyl-propane crystallizes in the shape of slightly yellow needles melting at 17 4 C. In the usual manner, preferably by catalytic hydration, it may be transformed into the pamino compound melting at C. The

hydrochloride of this base melts at 170171 C. The reactions are illustrated as follows:

H CHz-N nitrobenzoylchloride CB: OH;

3 dimethylamlno-2-lsopropyl-1- nitrobenz'oylhydroxypropane hydroc oride non-3H,

CH; C 3

3-dimethylamino-2-isoproEyl-1-pmmin0- benzoylhydroxypropane ydrochlorlde Example 6 Example 7 212 parts of 3-diethylamino-2-dimethylpropane-l-ol are dissolved in 318 parts of chloroform and a solution of 246 parts of o-nitrobenzoylchloride in 500 parts of chloroform is added drop by drop while cooling. After several hours standing the chloroform is distilled off. The hydrochloride of the o-nitrobenzoic acid ester of diethylaminodimethyl-propane remains as an oil easily soluble in water. By reduction with tin chloride and hydrochloric acid the o-amino compound is obtained in the usual manner, its hydrochloride crystallizes from acetone and melts at 130 C. The reactions are illustrated as follows:

5 parts of benzoic acid and 5 parts of 3- 0111--0 dimethylamino-2%dimethyl-propane-1-ol are kept for three hours under a continuous current of dry hydrochloric acid gas at 100 C. The melted product is then taken up in water, the excess of benzoic acid removed with ether, the aqueous part of the solution of sodium hydroxide made alkaline and treated with ether. After drying the ether 1s removed, the unchanged'starting base distilled off at 64 C. and 12 mm. pressure and after addition of alcoholic hydrochloric acid and 6%181 the residue is obt ined as hydrochlor1 e.

The compound forms colourless,

silvery leaflets melting at153 C. The reaction is illustrated as follows:

CH N

CH; C H: OH

hydrochloric acid Gil

3-dimethylamino-2- hcnzolc 5km dimethylpropane-l-ol CH: CHz-N C CH:

where R represents hydrogen or an alkyl radical, R representing an alkyl radical, and aromatic carboxylic' acids containing a benz zene nucleus, the new products forming well crystallized hydrochlorides, which are stable in hot water and have very strong anaesthetic properties.

011 /OH:N a 35 /O\ C1H|+CIC CHzOH 0: 3-dlethy1amino-2-dlmethylo-nltrobenzoylpropane-l-ol I chloride 3 I I I I 7 CH:\ /CH:N\ 1 I 0 can -HC1 I v on, 0H:0-0

' 5. v B-dlethylamlno-Z-dlmthyl-l-onltrobenzoylhydroxypropane hydrochloride on, CHr-N O CzHi -HCl+3Ha N02 9 3-diethylamino-2-dimethylo-nitrobenzoylhydroxypropane hydrochloride J can CH3\ /CH:-N

/0 Calls V-HCl+2H:0 CH: CH:OCO

| NH: 3 diethylamino 2-dimethyl-l-w aminobenzoylhydrorypropana hydrochloride I claim: 1. The esters of alcohol bases of the genv eral formula 4 R R\ /CH1N\ I R R CHrOH 2. The esters of alcohol bases of the general formula R CHrN g R/ cmon where Rue'presents hydrogen or an alkyl radical, R representing an alkyl radical, and carboxylic acids of the benzene series containing a nitro group or an amino group, the

new products forming well crystallized hydrochlorides which are stable in hot water,

and have very strong anaesthetic properties. 3. The compound 3-diethylamino-2-dimethyl-l p amino benzoylhydroxypropane,

which forms a well crystallized hydrochloride melting at 195-196 C., which is stable in hot water, and which has very strong anaesthetic properties.

4. The process for the manufacture of aromatic esters which consists in esterifying alcohol bases of the general formula Where R represents hydrogen or an alkyl radical, R representing an alkyl radical, with aromatic acids containing a benzene nucleus.

5. The process for the manufacture of aromatic esters which consists in esterifying alcohol bases of the general formula 40 R representing hydrogen or an alkyl radical, R representing an alkyl radical, with car boxylic acids of the benzene series containing a nitro group or an amino group.

6. The process for the manufacture of aromatic esters which consists in esterifying alcohol bases of the general formula R/ cmon R representing hydrogen or an alkyl radical, R representing hydrogen, with aromatic carboxylic acids containing a nitro-group, and

then reducing said nitro-group.

7. The process for the manufacture of 3- diethylamino-2-dimethyl-l-p-aminobenzoyl hydroxypropane, which consists in esterifying 3-diethylamino-2-dimethyl-propane-1-ol with p-nitrobenzoylchloride and reduction of the 3-diethylamino-Q-dimethyl-l-p-nitrobenzoylhydroxypropane.

In witness whereof I have hereunto set my hand.

CHARLES MANNICH.

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